Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases which include Alzheimer's disease and frontotemporal dementias, the hyperphosphorylation and aggregation of the microtubule (MT)-associated protein tau is believed to have pathological consequences via toxic gain and/or loss of functions. Recent studies from our laboratories have demonstrated that treatment with low weekly doses of the brain-penetrant MT-stabilizing agent, epothilone D (epoD), resulted in improved axonal transport, reduced axonal dystrophy and decreased neuronal pathology in tau transgenic (Tg) mice. These results thus suggest that compensation for the loss of tau MT-stabilizing function may be a viable therapeutic strategy for the treatment of tauopathies. However, epoD and related congeners have potentially significant deficiencies as drug candidates. Furthermore, epoD is the only example of a brain-penetrant MT-stabilizing agent that has undergone in vivo efficacy studies in tau Tg animal models. As a result, the development and evaluation of additional CNS-active MT-stabilizing agents is clearly desirable so as to identify alternative and improved clinical candidates. The focus of the proposed research plan is to investigate a related series of triazolopyrimidine, phenylpyrimidine, pyridopyridazine, pyridotriazine, and pyridazine MT-stabilizing compounds. After synthesis, compounds will be evaluated for MT-stabilizing activities, ADME-PK properties, and potential safety liabilities (Aim 1). The most promising MT-stabilizers (d15) found to be brain-penetrant and orally bioavailable will progress to an assessment of pharmacodynamic effect and acute toxicity (Aim 2), followed by longer-term 1-month safety assessments (Aim 3) to identify preferred candidates (1-2) that will undergo efficacy studies in an established Tg mouse model of tauopathy (Aim 4).